Diphenylmethyl compounds useful as muscarinic receptor antagonists

Abstract

This invention provides compounds of formula I: wherein a, b, c, e, m, R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , and R 8 are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

What is claimed is: 
     
       1. A pharmaceutical composition for inhaled administration comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  and R 2  are independently selected from (1–4C)alkyl, (2–4C)alkenyl, (2–4C)alkynyl, (3–6C)cycloalkyl, cyano, halo, —OR a , —SR a , —NR a R b , —S(O)R c  and —S(O) 2 R c ; where each R a  and R b  independently represents hydrogen, (1–4C)alkyl, (2–4C)alkenyl, (2–4C)alkynyl or (3–6C)cycloalkyl; each R c  independently represents (1–4C)alkyl, (2–4C)alkenyl, (2–4C)alkynyl or (3–6C)cycloalkyl; or two adjacent R 1  groups or two adjacent R 2  groups are joined together to form (3–6C)alkylene, (2–4C)alkylene-O— or —O-(2–4C)alkylene-O—; a and b each independently are 0 or an integer of from 1 to 5; 
 each R 3  independently is fluoro or (1–4C)alkyl; c is 0 or an integer of from 1 to 3; 
 R 4a  and R 4b  are independently selected from hydrogen, (1–4C)alkyl, and phenyl-(1–4C)alkyl; or R 4a  and R 4b  together with the nitrogen atom to which they are attached form a (3–6C)heterocyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen or sulfur and wherein the heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents selected independently from (1–4C)alkyl and fluoro; 
 e is 1 or 2; 
 m is 4, 5 or 6; 
 R 5  is selected from hydrogen, (1–4C)alkyl, and (3–4C)cycloalkyl; 
 R 6  is hydrogen or an unbranched (1–4C)alkyl; or R 6  and R 8  are joined, together with the atoms to which they are attached, to form a pyrrolidin-2-yl group; 
 R 7  is selected from hydrogen, (1–6C)alkyl, (3–6C)cycloalkyl, —CH 2 Ar 1 , —CH 2 CH 2 —OH and —CH 2 CH 2 —O-(1–4C)alkyl; wherein Ar 1  represents phenyl or (3–5C)heteroaryl, wherein the phenyl or heteroaryl group is unsubstituted or substituted with from 1 to 3 substituents selected independently from halo, (1–4C)alkyl and (1–4C)alkoxy, wherein each alkyl and alkoxy is optionally substituted with from 1 to 3 fluoro substituents; and 
 R 8  is hydrogen or (1–6C)alkyl; or R 7  and R 8  together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl or thiomorpholin-1-yl group; 
 wherein each alkyl group in R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8  and R a-c  is optionally substituted with from 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. 
 
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the composition further comprises a therapeutically effective amount of an agent selected from β 2  adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof. 
     
     
       3. The pharmaceutical composition of  claim 2 , wherein the composition comprises a therapeutically effective amount of a β 2  adrenergic receptor agonist and a steroidal anti-inflammatory agent. 
     
     
       4. The pharmaceutical composition of  claim 1 , which is in the form of an aerosol. 
     
     
       5. The pharmaceutical composition of  claim 1 , which is in the form of a powder. 
     
     
       6. The pharmaceutical composition of  claim 1 , wherein the compound is micronized. 
     
     
       7. The pharmaceutical composition of  claim 6 , wherein the compound is combined with the carrier to form a suspension. 
     
     
       8. The pharmaceutical composition of  claim 7 , wherein the carrier is an isotonic aqueous solution. 
     
     
       9. The pharmaceutical composition of  claim 6 , wherein the compound is combined with the carrier to form a free flowing powder. 
     
     
       10. The pharmaceutical composition of  claim 9 , wherein the carrier is lactose or starch. 
     
     
       11. The pharmaceutical composition of  claim 1 , which further comprises a liquefied propellant. 
     
     
       12. The pharmaceutical composition of  claim 1 , which is administered using a nebulizer inhaler. 
     
     
       13. The pharmaceutical composition of  claim 1 , which is administered using a metered-dose inhaler. 
     
     
       14. The pharmaceutical composition of  claim 1 , which is administered using a dry powder inhaler.